Increasingly in modern clinical chemistry, whole blood samples, often obtained by finger stick methods, are analyzed using automated automatic analysis systems (meters) which employ disposable (often one-time use) test elements, and a non-disposable electronic test device that analyzes the reaction occurring in the whole blood sample in the disposable test element, and then outputs an answer. Such systems are used for analyzing whole blood samples for glucose, cholesterol, and increasingly, more complex tests such as coagulation testing (prothrombin time, activated partial thromboplastin time), enzymatic analytes, and the like.
Because the answer from these devices are often used to make a clinical decision that can significantly impact the health and well-being of a patient, verification methods to insure that the analytical devices are performing correctly are of obvious importance.
One common method for verifying correct performance of a clinical analytical system is through the use of control solution, which is usually a liquid chemical solution with known reactivity. If the analytical device gives the correct answer with a known reference chemical, then the overall performance of the system can be assessed.
With modern one-shot, disposable test elements, however, the problem with liquid control testing is that it is destructive. The disposable test element has been destroyed as a result of the testing, and only the now-validated meter now survives to test the actual sample. For this reason, modern verification methods tend to shift validation of disposable test elements to manufacturers, who validate batches of disposable test elements by statistical sampling methods. The problem of meter verification remains, however. Meters are typically used for years, and can be exposed to environmental extremes, misuse, and mechanical shock.
Because meter verification using liquid control devices and disposable test units is an expensive process, and because test unit verification is inherently best suited to statistical lot testing by the manufacturer, there is a need for low-cost methods that can verify the performance of the meter without the use of liquid control solution and disposable test units.
Analytical devices for temperature sensitive enzymatic analytes, such as blood coagulation, typically have a temperature controlled reaction stage, means to determine the start of the enzymatic reaction, optical means to access the progress of the reaction, and computational means (typically a microprocessor or microcontroller) to interpret the progress of the reaction and output an answer. To completely verify the performance of the analysis system, each subsystem must be assessed. The temperature controlled reaction stage must be tested for proper temperature control, the means to determine the start of the enzymatic reaction must be tested for proper sensitivity, the optical means to access reaction progress must be tested (light source, light detector, integrity of optical stage, etc.), and finally the computational means must be tested. Alternatively partial verification of some of the subsystems may be done, and the remainder of the subsystems tested by alternate means, such as liquid control solution and a disposable test unit.
To verify the function of such analytical devices, electronic verification or "control" devices or circuits are commonly used. Such verification devices can simulate the action of an enzymatic sample interacting with a disposable reagent. If the analytical device returns the proper answer after analysis of the verification device, then the proper functioning of the analytical device can be verified without the expense of using the one time use reagent cartridges.
The use of reference paint chips to calibrate and verify photometric devices has long been known in the art. When applied to home blood glucose monitors, such reference chips are often referred to as "check strips". For example, the LifeScan One-Touch.TM. blood glucose monitor includes a colorimetric "check strip" in with its meter system. This "check strip" consists of an opaque plastic strip with a paint chip of known colorimetric properties affixed to it. The check strip is inserted into the meter, and is used to verify the performance of the meter's colorimetric photodetector. The system does not vary the intensity of the colorimetric paint chip target as a function of time to simulate a normal test reaction, nor does it incorporate means to monitor the analytical devices' temperature.
Recent refinements to the basic "paint chip" technique, suitable for clinical reagents and instrumentation, include U.S. Pat. Nos. 4,509,959; 4,523,852; 4,729,657; 5,151,755; 5,284,770; and 5,592,290. 4,509,959 disclosed an apparatus incorporating many such reference color chips. U.S. Pat. No. 4,523,852 disclosed a reference standard, suitable for visually read diagnostic reagent test strips, consisting of many colored reference areas of differing hues. U.S. Pat. No. 4,729,657 disclosed photometer calibration methods using two or more reflectance standards and using least squares regression line analysis to construct and store calibration curves in the analytical device's memory. U.S. Pat. No. 5,151,755 disclosed methods to detect defects in biochemical analysis apparatuses measurement means by irradiating a reference density plate with light that has passed through a plurality of interference filters and comparing the relative amounts of reflected light obtained by these different measurements. U.S. Pat. No. 5,284,770 disclosed use of a check strip, along with an analytical instrument having a user insertable key (memory chip) containing the parameters of acceptable check strip performance, so that correct instrument performance can be automatically verified. U.S. Pat. No. 5,592,290 disclosed optical analyzer instrument error correction methods using standard color plates incorporating dyes with absorption spectrum similar to the analytical reagent normally read by the analyzer. These standard color plates are then used in conjunction with a second reference optical analyzer and a specific correction algorithm to correct the instrument error in the first instrument.
In addition to passive "paint chip" verification methods, a number of different active (typically electronic) verification methods have also been used. These active verification methods typically involve electronic components, and often produce a dynamic (as opposed to a static) reference signal to the analytical instrument.
U.S. Pat. No. 4,454,752 disclosed a test circuit for use in a photometric coagulation instrument for plasma samples that verified the electronic circuitry of the instrument, wherein the rapid rise in clot density of a plasma sample may be simulated by a applying to the clot detection circuitry of the instrument a synthetic waveform that simulates the signal that results during clot formation in a reagent plasma mixture. However, this patent did not disclose methods by which the proper functioning of an instrument capable of measuring whole blood can be analyzed. The disclosed methods are capable of verifying only that the clot detection circuits of an photometric plasma coagulation instrument are performing properly. The patent did not disclose methods by which other instrument functions such as temperature control, absence of optical system light leaks, proper detection of sample insertion, etc., may also be verified.
Verification methods suitable for partially verifying the function of certain whole blood coagulation analyzers and unitized reagent cartridges are also known in the art. For example, U.S. Pat. Nos. 4,948,961 and 5,204,525 disclosed a quality control device for an instrument with an analysis cartridge constructed so that the instrument's light passes through the cartridge's internal chamber. Such systems have been used for a number of whole blood clinical tests, including whole blood prothrombin time assays when the internal chamber is filled with thromboplastin, and the cessation of red cell movement is tracked by light scattering techniques.
U.S. Pat. No. 5,204,525 disclosed a control device using a liquid crystal cell interposed between the light source and detector in an analytical instrument, and a polarizing filter, so that the passage or block passage of light between the analytical device's light source and light detector when the voltage to the liquid crystal is modulated. However, neither U.S. Pat. No. 5,204,525 nor U.S. Pat. No. 4,948,961 disclosed means by which the temperature control of an analytical device may be verified. Although these publications disclosed devices useful for monitoring the function of optically transmissive reaction chambers in which the light source passes through the chamber, and which the reaction in question does not alter the wavelength of the light emitted by the instrument's light source, they did not disclose devices useful for monitoring the function of fluorescent test strip articles such as those disclosed in U.S. Pat. No. 5,418,143. In such systems, light of one wavelength enters a test strip, and excites a fluorescent compound which then emits light that exits the test strip at the same side as the light source (rather than passing through a reaction chamber), and at a different wavelength.
Another type of control device is found in the Boehringer Mannheim "Coaguchek" whole blood prothrombin time analysis device disclosed by U.S. Pat. No. 4,849,340. This device uses a disposable reagent cartridge consisting of a chamber with thromboplastin and magnetic particles. The disposable reagent cartridge is placed in a stage in the analysis device, and a blood sample is added. The analysis device subjects the reagent cartridge to a varying magnetic field, and detects the motion of the magnetic particles by the optical interaction between the motion of the magnetic particles and a beam of light. In normal operation, when blood is applied to the disposable reagent cartridge, the magnetic particles are free to move in suspension, and thus provide a high degree of modulation to the optical signal in response to the varying magnetic field. As the blood clots in response to the thromboplastin reagent, the magnetic particles become less able to move, and thus provide a progressively smaller amount of modulation to the optical signal as time progresses.
An "electronic control" is provided for the Coaguchek. (Boehringer Mannheim electronic control user manual, 1996). This "electronic control" consists of a separate device consisting of a disposable reagent sized probe that fits in to the reagent stage on the Coaguchek device. The probe contains a magnetic coil pickup, a light emitting diode, and means to vary the intensity of the response of the light emitting diode to current generated by the magnetic coil pickup. By using this "electronic control" device, the operator can verify that the varying magnetic field generator on the Coaguchek is operating properly, and that the optical sensor on the Coaguchek is also operating properly. The temperature of the reaction stage, and the performance of the optical light source on the Coaguchek, are not tested by this device, however.
In addition to passive (time unvarying reference signal) and active (time varying reference signal) verification devices, a third type of verification methodology has been disclosed which incorporates certain verification systems on to the disposable reagent itself. This is disclosed by in U.S. Pat. Nos. 5,591,403 and 5,504,011. U.S. Pat. No. 5,591,403 disclosed a reaction chamber cuvette, useful for prothrombin time testing, with multiple conduits. One or more conduits contain the reaction chemistry for the prothrombin time reaction itself, and other conduits contain control agents useful for assessing certain functions of the analytical instrument that reads the test cartridge, and the test cartridge itself. Typically one "control" conduit will contain a vitamin K dependent clotting factor concentrate, and a different "control" conduit will contain an anticoagulant. In a properly functioning instrument, the control conduit with the vitamin K dependent clotting factor concentrate will initiate a coagulation signal early, and the control conduit with the anticoagulant will initiate a coagulation signal late. This tests the proper function of those meter detector elements that read the status of the control conduits. Because the control elements are incorporated into normal prothrombin time reaction cuvette, an independent, non-destructive, test of proper meter function is not possible with this system.
Thus, a need exists for an improved verification device. This need and others are addressed by the instant invention.